Gene Therapy Works in SCID With No Risk of Leukemia

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Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

NEW ORLEANS -- A next generation genetic therapy appeared to restore the immune system of patients with "bubble boy disease," but without leading to leukemia as a side effect, researchers reported here.

"We are 3 years' post-therapy for some of these children, and have not seen any sign of leukemia," Pai said at the American Society of Hematology annual meeting. "But the emergence of leukemia occurred in the 3- to 5-year time frame in the previous trial. We still have to wait."

The current standard treatment for X-SCID is hematopoietic stem cell transplantation, but finding a suitable donor is problematic.

"Without curative therapy such as bone marrow transplantation, these boys die of opportunistic or community-acquired viral infection," Pai said. "Outcomes for boys who do not have well-matched donors are suboptimal. For these patients, gene therapy is an attractive option."

The work by Pai and colleagues is similar to previous attempts with genetic therapy in this fatal disease. In the French trial that Pai mentioned, 18 of 20 boys treated with a MLV-based gammaretroviral vector achieved reconstituted immune systems, but five developed T-cell acute lymphoblastic leukemia. One patient died while the others recovered with treatment; these patients are alive and now have normal T-cell numbers and diversity, Pai's group reported.

For their ongoing phase I/II trial, the current authors wanted to test a SIN gammaretroviral vector that would promote T-cell reconstitution in boys with X-SCID with an improved safety profile.

Pai explained that leukemia cases most likely emerged because the inserted gene caused oncogenes to activate. "The same genetic material that drives the gene of interest to repair the immune system is also turning on other genes inappropriately," she told MedPage Today. "In our new vector, we used a cell-derived promoter that was weaker so that it would not also turn on neighboring genes."

For this therapy, the missing gene was transferred by way of a retroviral vector into cells harvested from the patient's bone marrow. The cells were then re-infused into the patient.

All nine patients received bone marrow-derived CD34+ cells transduced with the vector and infused without conditioning. Transduction efficiency of infused CD34+ cells ranged from 0.25-2.92 vector copy number (VCN).

One patient with a low initial transduction underwent a repeat procedure 1 month after infusion of the first product. Another patient experienced treatment failure and underwent hematopoietic stem cell transplantation.

Seventy-one percent of the patients achieved CD3+ T cell count >300/mcl. The two patients who did not achieve T cell count >300/mcl received CD34+ cells with the lowest VCN, the authors explained.

"At last follow-up, the remaining seven patients have evidence of [gamma chain] transgene expression in T cells, naive T-cell generation, and normal diversity. They are free of SCID-related infections, and humoral immune evaluation is ongoing," the authors wrote.

Pai's group also did an early immune recovery and peripheral blood insertion site analysis between six patients from their trial and the 20 subjects enrolled in the earlier study.

They found that the CD3+ T cell count at 6 months for their patients was a median 548/mcl versus a median 1,755/mcl for those in the earlier study (P=0.14 in two-sided Wilcoxon rank sum test).

"However, we recognize that this test is underpowered, and results are preliminary," they said.

ASH press conference moderator, Laurence Cooper, MD, PhD, warned that "these are emerging data, so we have to be cautious ... in the prior experience from France in which the kids were treated with a kissing cousin of the new vector, we learned very quickly and sadly that this vector ... fired off these oncogenes."

But Cooper, who is director of pediatric care at the University of Texas MD Anderson Cancer Center in Houston, acknowledged that "genetically-engineered cell therapies may provide a vital lifeline for patients who haven't yet responded to other treatments. Dr. Pai and colleagues administered a gene vector that included a crucial missing bit of genetic material. The new strategy doesn't necessarily change the way the vector integrates; it just changes the ability of the vector to fire these transcripts. We will have to see over time how well these kids do."

He added that "at the moment, I would go to transplantation and wait for these data to mature. The competing technology now is allogeneic bone marrow transplantation where you go to a sibling donor or an unrelated donor. That can be lifesaving itself and is well-established. It's an uphill battle for genetic therapy, but if they can prove the technology works, I think you will see the pendulum swing that way."

Pai pointed out several advantages to gene therapy including the fact that the patient serves as his own donor, "so there is no chance of immunologic rejection or graft-versus-host disease."

Also, there is no preparatory conditioning required which can be advantageous when treating infants as "the age of typical presentation of SCID is between 3 and 9 months," Pai said.

Finally, she explained that "while the testing and preclinical efficacy work for these vectors can take months to years, once we know what vector we need for a specific child, the blood marrow can be harvested on Monday and the child can be infused on Friday."

The authors reported off-label use of the CliniMACS device for purification of CD34+ bone marrow cells.

Pai reported no conflicts of interest. One co-author reported receiving royalties and holding patents with the Transatlantic Gene Therapy Consortium.